The drug rivastigmine is prescribed for the treatment of dementia of the Alzheimer's type and dementia associated with Parkinson's disease. The active drug compound has the following structure, and acts as an inhibitor of the enzyme acetylcholinesterase (AChe) involved in the breakdown of neurotransmitter acetylcholine.

Inhibition of AChe increases the half-life of acetylcholine released into synaptic clefts, thereby enhancing cholinergic neurotransmission. Rivastigmine shows substantially greater inhibition of AChE in the central nervous system (CNS) compartment than in the periphery (see Polinsky, R. J., 1998, Clinical Therapeutics 20(4):634-647). Moreover, rivastigmine preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer's disease (AD).
Various methods have been described for synthesis of rivastigmine. U.S. Pat. No. 4,948,807 describes a process for preparation of racemic rivastigmine by reacting an m-hydroxyphenylisopropyldimethylamine or an m-hydroxyphenylethyldimethylamine with carbamoyl chloride in the presence of NaH. Process for resolution of the racemic product is described in U.S. Pat. No. 5,602,176, which involves chiral resolution using di-o,o′-p-toluoyl tartaric acid.
Patent publication WO03/101917 describes a process for preparation of rivastigmine by condensing N-ethyl-N-methyl-4-nitrophenyl carbamate, which is obtained by demethylation of [1-(3-methoxyphenyl)ethyl]dimethylamine, in the presence of base.
Patent publication WO2004/037771 describes reductive amination of 3-methoxy acetophenone in presence of dimethylamine, titanium isopropoxide and sodium borohydride to obtain [1-(3-methoxyphenyl)ethyl]dimethylamine, which is further demethylated using hydrobromic acid to obtain 3-(1-dimethylamino)phenol. This is further resolved using (S)-(+)camphor-10-sulfonic acid and reacted with carbamoyl chloride to obtain rivastigmine.
Patent publication WO2006/068386 describes a process for preparation of 3-(1-dimethylamino)phenol by subjecting (S)-3-(1-dimethylaminoethyl)phenol to N-methylation using formaldehyde/formic acid. The 3-(1-dimethylamino)phenol it is subjected to O-carbamoylation to form rivastigmine.
Patent publication WO2008/020452 describes N-methylation using paraformaldehyde in the presence of Raney Nickel and hydrogen in a suitable solvent to obtain 3-(1-(dimethylamino)ethyl)phenol (see also Hu et al., 2007, A Simple and Efficient Synthesis of (S)- and (R)-1-(3-Methoxyphenyl)Ethylamine, Lett. Org. Chem. 4(2):126-128).
Enzyme based synthesis of rivastigmine is described in Mangas-Sanchez, 2009, Chemoenzymatic Synthesis of Rivastigmine Based on Lipase-Catalyzed Processes,” J. Org. Chem., 74 (15):5304-5310. The described process uses a lipase for the acetylation of 1-(3-methoxyphenyl)ethanol or 1-(3-methoxyphenyl)ethylamine. The desired isomer is isolated and chemically converted to (S)-1-(3-methoxyphenyl)ethanol or (S)-1-(3-methoxyphenyl)ethylamine and then to (S)-3-(1-dimethylamino)phenol.
There is a need for improved transaminase biocatalysts that can be used to prepare the intermediate compounds for making rivastigmine, related chiral amine compounds, and new processes employing those biocatalysts that are simple, cost effective, non-hazardous, and commercially viable.